EP1649045A2 - Incorporation de groupes haptene lors de la production de supports pour la determination de substances a analyser - Google Patents

Incorporation de groupes haptene lors de la production de supports pour la determination de substances a analyser

Info

Publication number
EP1649045A2
EP1649045A2 EP03813913A EP03813913A EP1649045A2 EP 1649045 A2 EP1649045 A2 EP 1649045A2 EP 03813913 A EP03813913 A EP 03813913A EP 03813913 A EP03813913 A EP 03813913A EP 1649045 A2 EP1649045 A2 EP 1649045A2
Authority
EP
European Patent Office
Prior art keywords
hapten
synthesis
carrier
receptor
support
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP03813913A
Other languages
German (de)
English (en)
Other versions
EP1649045B1 (fr
Inventor
Markus Beier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Febit Holding GmbH
Original Assignee
Febit Biotech GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10260592A external-priority patent/DE10260592A1/de
Priority claimed from DE10260591A external-priority patent/DE10260591A1/de
Priority claimed from DE10320339A external-priority patent/DE10320339A1/de
Application filed by Febit Biotech GmbH filed Critical Febit Biotech GmbH
Publication of EP1649045A2 publication Critical patent/EP1649045A2/fr
Application granted granted Critical
Publication of EP1649045B1 publication Critical patent/EP1649045B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/0059—Sequential processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623—Immobilisation or binding
    • B01J2219/00626—Covalent
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00693—Means for quality control
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2565/00—Nucleic acid analysis characterised by mode or means of detection
    • C12Q2565/60—Detection means characterised by use of a special device
    • C12Q2565/629—Detection means characterised by use of a special device being a microfluidic device

Definitions

  • the invention relates to a method for producing a carrier, in particular a microfluidic carrier, for the determination of analytes.
  • the biophysical principle on which the receptor arrays are based is that of the interaction of a specific immobilized receptor with an analyte present in a liquid phase, for example by nucleic acid hybridization, a large number of receptors, e.g. Hybridization probes are attached, each with different analytes present in the sample, e.g. B. complementary nucleic acid analytes, bind specifically.
  • a carrier and a method for analyte determination which allow integrated receptor synthesis and analysis are e.g. described in WO 00/1 301 8.
  • the receptor synthesis there is preferably carried out using photoactivatable receptor building blocks.
  • a synthesis of the receptor building blocks by wet chemical methods is also disclosed.
  • DE 101 22 357.9 describes a method for receptor synthesis which includes the use of a combination of photochemical and wet chemical steps.
  • a first aspect of the invention is a method for producing a support for the determination of analytes, comprising the steps: (a) providing a support, (b) passing liquid with building blocks for the synthesis of polymeric receptors over the support,
  • Hapten groups are incorporated into the receptor molecules at predetermined positions during synthesis,
  • the present invention is characterized in particular in that the method for producing the carrier can be integrated with a detection system for analyte determination.
  • This detection system can be used for integrated synthesis and analysis, in particular for the construction of complex supports, e.g. Biochips, and for analysis of complex samples, e.g. for genome, gene expression or proteome analysis.
  • the synthesis of the receptors takes place in situ on the carrier, for example by passing fluid with receptor synthesis building blocks over the carrier, the building blocks are immobilized on the support at the respectively predetermined areas in a location-specific and / or time-specific manner and these steps are repeated until the desired receptors have been synthesized on the respective predetermined areas on the support.
  • hapten groups are flat or / and spatially resolved, before, during or / and at the end of a spacer structure - which takes place before the actual receptor structure - and / and before, during and / and at the end of the receptor synthesis the carrier can be applied.
  • the carrier produced by the method according to the invention is preferably integrated in a device for determining analytes, comprising (i) a light source matrix, preferably a programmable light source matrix, e.g. selected from a light valve matrix, a mirror array, a UV laser array and an LED array, (ii) a carrier, preferably a microfluidic carrier with channels, in particular with closed channels, in which the predetermined areas with the differently immobilized receptors are located, wherein the channels are preferably in the range from 10 ⁇ m to 10000 ⁇ m, particularly preferably in the range from 50 to 250 ⁇ m, and can in principle be configured in any form, for example with round, oval, square or rectangular cross-section,
  • the carrier offers the possibility of determining the site-specific immobilization by dividing it into fluidic subspaces that can be addressed separately from one another.
  • a carrier that fulfills this criterion is described in WO 00/1301 8.
  • the carrier offers the division of the reactive areas into 2 or more subspaces.
  • the receptors are preferably selected from biopolymers which can be synthesized in situ on the support from the corresponding synthetic building blocks by a combination of light-controlled and wet-chemical processes. Both monomeric, e.g. Mononucleotides, amino acids etc., as well as oligomeric building blocks, e.g. Di-, tri- or tetranucleotides, di-, tri- or tetrapeptides etc. can be used.
  • the receptors are preferably selected from nucleic acids such as DNA, RNA, nucleic acid analogs such as peptide nucleic acids (PNA), proteins, peptides and carbohydrates.
  • the receptors are particularly preferably selected from nucleic acids and nucleic acid analogs and used in a detection method for hybridizing complementary nucleic acid analytes.
  • the receptors are preferably immobilized on the surface via spacer groups. Spacer groups can also be built up step by step from corresponding synthetic building blocks.
  • the spacer or receptor synthesis preferably comprises the use of synthesis components with wet-chemical protective groups or / and of receptor components with photochemical protective groups. If necessary, it is also possible to use synthetic building blocks which carry both wet-chemical and photochemical protective groups or hybrid protective groups, ie groups which can be split off in two stages by a wet-chemical and a photochemical step.
  • wet chemical protective groups are any protective groups, such as from the prior art for the synthesis of biopolymers, such as Nucleic acids or peptides are known on solid supports. Preferred examples are acid-labile protective groups, base-labile protective groups, protective groups labile to oxidation or enzymatically cleavable protective groups.
  • the method according to the invention preferably comprises the production of a carrier with several, preferably with at least 50 and particularly preferably with at least 100 different receptor regions which can react with different analytes in a single sample.
  • the method according to the invention can be used to produce carriers, the receptors in each region of the carrier containing only a single sequence of building blocks. In a further embodiment, however, the method according to the invention can also be used to produce carriers, the receptors in at least one region of the carrier containing several different sequences of building blocks.
  • the method according to the invention includes the application of hapten groups to the support used for the production of receptors.
  • hapten groups are preferably selected from organic molecules with a molecular weight of up to 2,000, in particular up to 1,000, which are derived from a specific binding partner, for example a protein, such as such as an antibody, streptavidin, avidin or a lectin, can be recognized by a high affinity interaction.
  • a specific binding partner for example a protein, such as such as an antibody, streptavidin, avidin or a lectin.
  • the term "high affinity interaction" in this context means that the interaction between the hapten group and binding partner is sufficiently strong to enable control of the incorporation of hapten groups on the support under the respective operating conditions with an appropriate detection reagent.
  • haptens are digoxin and digoxigenin and dinitrophenol (DNP), which are recognized by appropriate antibodies, or biotin or biotin analogs, such as iminobiotin, aminobiotin or desthiobiotin, which are recognized by streptavidin and avidin.
  • DNP digoxin and digoxigenin and dinitrophenol
  • the hapten groups can be applied to the support in a flat or site-specific manner. Combinations of flat application and site-specific application, for example using two or more different hapten groups, are also possible.
  • surface application means that hapten groups are applied to the entire surface of the support or a part thereof, which contains areas for receptor synthesis and adjacent areas on which no receptor synthesis is to take place.
  • site-specific application means that the hapten groups are applied selectively to individual areas or groups of areas for receptor synthesis.
  • the hapten groups are introduced into a spacer.
  • a spacer is arranged between the actual carrier surface and the receptor and can serve to adjust the distance of the receptor from the surface or the receptor density to an optimal value within the predetermined ranges.
  • the spacers are preferably also synthesized by site-specific and / or time-specific immobilization of individual spacer units until the desired spacers are in the respectively predetermined areas have been synthesized.
  • the chemistry of the spacer structure can be carried out analogously to the chemistry of receptor synthesis using analog building blocks which, however, do not contain any receptor elements, for example by using phosphoramidite building blocks without nucleobases.
  • the hapten group can be applied over the entire surface of the carrier.
  • a receptor synthesis is then optionally carried out together with a spacer synthesizer according to the known method and the surface of the support is then stained by the hapten binding partner. In areas where successful receptor synthesis has taken place, the binding partner cannot stain. The degree of lack of staining correlates with the receptor density.
  • This procedure also has the advantage that the receptors used for the analyte determination carry a hapten group and the hapten group cannot have a disruptive effect in the subsequent analyte determination.
  • the hapten groups are introduced at one or more positions in the receptors synthesized on the carrier, for example at the beginning, in the middle or at the end of the receptor. This procedure allows the efficiency of receptor synthesis to be controlled via the number of hapten groups introduced into a region.
  • the introduction of the hapten groups can be reversible or irreversible.
  • a reversible introduction of the hapten groups has the advantage that the groups can be split off again at defined times during or after the receptor synthesis and therefore cannot impair the analyte binding to the receptor.
  • FIG. 1B shows a phosphoramidite building block which is modified with a diisopropylamino group, a hapten group optionally bonded to the phosphorus atom via a spacer and a group O-Y, where Y can contain a spacer group or a nucleobase.
  • the hapten function is directly linked to the phosphitamide unit.
  • FIG. 2 shows specific embodiments of the phosphoramidite derivative shown in FIG. 1A. In those shown in Figures 2A and D,
  • the hapten group is a dinitrophenyl group.
  • the hapten group is a biotin group.
  • the hapten group is one
  • FIGS. 2A-C are suitable for reversible monitoring, while the derivatives shown in FIGS. 2D-F can be used for irreversible monitoring.
  • Figure 3 shows specific examples of the derivative shown in Figure 1B.
  • a dinitrophenyl group is present as the hapten group.
  • group Y is a spacer group, R being a protective group, for example a photolabile or acid-labile protective group.
  • Y is a nucleoside group comprising a deoxyibose unit and nucleobase (B), the 5 ′ position of the deoxyribose unit being blocked by a protective group R.
  • Both reagents are also suitable for internal labeling of an oligonucleotide with haptens.
  • the compounds according to FIG. 3A are produced in accordance with the synthesis scheme in FIG. 3C.
  • the connection according to FIG. 3B is produced in accordance with the synthesis scheme in FIG. 3D, the nucleobase being e.g. T is used.
  • DNP DNP group
  • T thymidine unit
  • the detection was carried out with an anti-DNP antibody which was labeled with Alexa-488. Only those positions give a signal to which a DNP unit has been condensed. The signal strength depends on the antibody concentration.
  • a module of type 2A was used as the DNP group, ie reversible monitoring was carried out. After abstraction of the at the DNP unit located DMT group, the receptor synthesis could be continued.
  • FIG. 5 shows the two-dimensional coupling of two spacer units (X) and the final two-dimensional application of DNP on the support before a spatially resolved receptor synthesis of homomeric thymidine units.
  • a building block of the type according to FIG. 2A was used as the DNP group, i.e. reversible monitoring was carried out. After abstraction of the DMT group located on the DNP unit, the receptor synthesis could be continued.
  • the length of the built-up oligonucleotides can thus be determined by reaction with the anti-DNP antibodies. This means that this method is suitable for quality control of a receptor synthesis, since the detection of the probe length and thus also the efficiency of the synthesis carried out at this position can take place universally regardless of a sequence with an antibody. Instead of a control hybridization, which requires knowledge of the receptor sequences that have been built up, any number of different sequences can be recognized universally via the antibody.
  • the support shown in FIG. 5 with oligo-T receptors can easily be used for hybridization experiments, for example with fluorescence-labeled dA 15 probes. A signal intensity dependent on the length of the T probe is obtained.
  • FIG. 6 shows the incorporation of biotin groups in a spacer. After the spatially resolved coupling with 1 to 4 spacer units (X ... XXXX) a biotin group was introduced, either:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé pour la production d'un support, notamment d'un support microfluidique, destiné à la détermination de substances à analyser.
EP03813913A 2002-12-23 2003-12-23 Incorporation de groupes haptene lors de la production de supports pour la determination de substances a analyser Expired - Lifetime EP1649045B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10260592A DE10260592A1 (de) 2002-12-23 2002-12-23 Intramolekular triplettsensibilisierte o-Nitrophenylethyl-Photoschutzgruppen
DE10260591A DE10260591A1 (de) 2002-12-23 2002-12-23 Photoaktivierbare zweistufige Schutzgruppen für die Synthese von Biopolymeren
DE10320339A DE10320339A1 (de) 2003-05-07 2003-05-07 Einbau von Hapten-Gruppen bei der Herstellung von Trägern für die Analytbestimmung
PCT/EP2003/014820 WO2004059003A2 (fr) 2002-12-23 2003-12-23 Incorporation de groupes haptene lors de la production de supports pour la determination de substances a analyser

Publications (2)

Publication Number Publication Date
EP1649045A2 true EP1649045A2 (fr) 2006-04-26
EP1649045B1 EP1649045B1 (fr) 2008-06-25

Family

ID=32685656

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03813913A Expired - Lifetime EP1649045B1 (fr) 2002-12-23 2003-12-23 Incorporation de groupes haptene lors de la production de supports pour la determination de substances a analyser

Country Status (5)

Country Link
US (1) US20060105388A1 (fr)
EP (1) EP1649045B1 (fr)
AU (1) AU2003296723A1 (fr)
DE (1) DE50310049D1 (fr)
WO (1) WO2004059003A2 (fr)

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
DE102005027667A1 (de) * 2005-06-15 2006-12-28 Febit Biotech Gmbh Verfahren zur Qualitätskontrolle funktionalisierter Oberflächen

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US6555310B1 (en) * 1997-04-04 2003-04-29 Biosite Diagnostics, Inc. Polyclonal libraries
ATE296677T1 (de) * 1998-08-28 2005-06-15 Febit Ag Träger für analytbestimmungsverfahren und verfahren zur herstellung des trägers
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AU2002216614A1 (en) * 2000-10-03 2002-04-15 Minerva Biotechnologies Corporation Electronic detection of interaction based on the interruption of flow
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Also Published As

Publication number Publication date
AU2003296723A1 (en) 2004-07-22
DE50310049D1 (de) 2008-08-07
US20060105388A1 (en) 2006-05-18
AU2003296723A8 (en) 2004-07-22
WO2004059003A2 (fr) 2004-07-15
WO2004059003A3 (fr) 2006-03-30
EP1649045B1 (fr) 2008-06-25

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